US 8,871,778 B2 · Substituted pyrimidine compounds and their use as SYK inhibitors

Abstract

Compounds of Formula (I) and methods for inhibiting kinases, including spleen tyrosine kinases, are disclosed. Also disclosed are methods for treating a kinase-mediated disease or condition by administering to a subject a therapeutically effective amount of the compound of Formula (I).

A compound of Formula (I):

Wherein:
X is CH or N
is a single or a double bond;
A is C;
B is C;
E is C;
R1 is selected from H, C1-C6alkyl, C3-C7cycloalkyl, C5-C8heterocycloalkyl, aryl, arylalkyl, heteroaryl, C(O)NR7R7C(O)R7, S(O)nR7, S(O)nNR7R7, C(O)NR8R9, or S(O)nNR8R9, wherein each n is 1 or 2 and the C1-C6 alkyl, C3-C7cycloalkyl, C5-C8heterocycloalkyl, aryl, arylalkyl, or heteroaryl is optionally substituted with one or more halo, amino, hydroxy, OR7, NHR7, NR7R7, NR8R9, or C3-C7cycloalkyl;
R8 and R9, taken together with the nitrogen atom to which they are bonded form:
i) a 3-8 membered saturated or partially saturated monocyclic group having no heteroatom other than the nitrogen atom to which R8 and R9 are bonded, wherein said 3-8 membered saturated or partially saturated monocyclic group is optionally and independently substituted at one or more carbon atoms with halo, amino, hydroxy, R7, OR7, SR7, NHR7, NR7R7, or NR8R9;
or
ii) a 5-8 membered saturated or partially saturated monocyclic group having 1 or 2 heteroatoms selected from nitrogen, oxygen, sulfur, sulfone or sulfoxide, wherein said 5-8 membered saturated or partially saturated monocyclic group having 1 or 2 heteroatoms is optionally substituted with R7;
R2 is selected from H, halo, CF3, C1-C4alkyl or aryl, wherein the C1-C4alkyl or aryl is optionally substituted with one or more halo, amino, hydroxy, alkoxy, or haloalkyl;
R3 is selected from C(O)NR7R7, C(O)R7, S(O)nR7, S(O)nNR7R7, C(O)NR8R9, or S(O)nNR8R9, wherein each n is 1 or 2;
R4 is selected from H, halo, C1-C6alkyl, C3-C7cycloalkyl, wherein the C1-C6alkyl, or C3-C7cycloalkyl is optionally substituted with one or more halo, amino, hydroxy, alkoxy, or haloalkyl;
R5 is selected from H, halo, C1-C6alkyl, CF3, CN, C3-C7cycloalkyl, aryl or C5-C8heteroaryl , wherein C3-C7cycloalkyl, aryl or C5-C8heteroaryl is optionally and independently substituted with one or more halo, amino, hydroxy, alkoxy, or haloalkyl;
R6 is selected from CH2OH, (CH2)nNH2, (CH2)nOR7, (CH2)nNHR7, (CH2)nNR7R7, (CH2)nNR7R10, C(O)NHR7, C(O)NR7R7, C(O)NR7R10, (CH2)nC(O)OR7, C(O)R7, (CH2)nNHS(O)nR7, (CH2)nNR7S(O)nR7, (CH2)nNR11R12, C(O)NR11R12, or (CH2)nCN, wherein each n is independently 1 or 2;
R7 is independently selected from C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C7cycloalkyl, aryl, aryl(C1-C4)alkyl, haloalkyl, heteroaryl, or heterocyclyl, wherein the C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C7cycloalkyl, aryl, aryl(C1-C4)alkyl, haloalkyl, heteroaryl, or heterocyclyl is optionally and independently substituted with one or more aryl, cycloalkyl, heteroaryl, heterocyclyl, alkyl, halo, amino, hydroxy, or R13;
Each R10 is independently selected from C(O)R7, C(O)OR7, C(O)NR7R7 or S(O)nR7, wherein n is 1 or 2;
Each R13 is independently selected from SR7, OR7, NR7R7, C(O)NR7R7, S(O)nNR7R7, S(O)nR7, NR8R9, or C(O)R8R9, wherein each n is independently 1 or 2;
R11 and R12, taken together with the nitrogen atom to which they are bonded form:
i) a 3-8 membered saturated or partially saturated monocyclic group having no heteroatom other than the nitrogen atom to which R11 and R12 are bonded, wherein said 3-8 membered saturated or partially saturated monocyclic group is optionally and independently substituted at one or more carbon atoms with R14, wherein R14 is COOH, COOR7, CN, (CH2)nOH, (CH2)nOR7, halo, amino, hydroxy, R7, OR7, SR7, NHR7, NR7R7, NR8R9, NHC(O)NHR7, NHC(O)NR7R7, OC(O)R7, NHC(O)NR8R9, NHS(O)nR7, NHS(O)nNHR7, wherein n is 1 or 2;
or
ii) a 5-8 membered saturated or partially saturated monocyclic group having 1 or 2 heteroatoms selected from nitrogen, oxygen, sulfur, sulfone, or sulfoxide, wherein said 5-8 membered saturated or partially saturated monocyclic group having 1 or 2 heteroatoms is optionally substituted with R7;
or a pharmaceutically acceptable salt thereof.

21 more elements

Substituted pyrimidine compounds and their use as SYK inhibitors

Life of this patent

Substituted pyrimidine compounds and their use as SYK inhibitors

Life of this patent

Abstract

Claims20